1. Field of the Invention
The present invention relates to methods for modulating calcium sensitivity of cardiac muscle. In preferred aspects, the invention provides methods for enhancing myocardial contractility and cardiac performance, and methods for treatment of heart failure and other disorders associated with cardiac contractility by administration of one or more compounds that can increase cardiac contractility such as a xanthine oxidase inhibitor compound. The invention also provides methods for increasing cardiac contraction efficiency through administration of a xanthine oxidase inhibitor.
2. Background
Heart failure afflicts more than two million Americans, and congestive heart failure is recognized as the most common cause of hospitalization and mortality in Western society.
Congestive heart failure is a syndrome characterized by left ventricular dysfunction, reduced exercise tolerance, impaired quality of life and dramatically shortened life expectancy. Decreased contractility of the left ventricle leads to reduced cardiac output with consequent systemic arterial and venous vasoconstriction.
Captopril, enalapril and other inhibitors of angiotensin-converting enzyme (ACE) have been used to treat congestive heart failure. See Merck Index, 1759 and 3521 (11th ed. 1989); Kramer, B. L. et al. Circulation 1983, 67(4):755-763. However, such ACE inhibitors have generally provided only moderate or poor results. For example, captopril therapy generally provides only small increases in exercise time and functional capacity. Captopril also has provided only small reductions in mortality rates.
It thus would be desirable to have new therapies for treatment of heart failure.
The present invention includes methods for modulating, particularly increasing, calcium sensitivity of cardiac muscle. That is, the invention provides new methods for increasing contractile force of cardiac myofilaments, while decreasing intracellular calcium concentrations.
It has been surprisingly found that administration of a compound that can increase cardiac contractility, particularly a xanthine oxidase inhibitor compound, can sensitize cardiac muscle to intracellular calcium, and thus enable treatment of disorders associated with cardiac contractility. See, for instance, the results of the examples which follow.
Additionally, it has been unexpectedly found that xanthine oxidase inhibitor compounds can improve efficiency of cardiac contraction. In particular, it has been found that a xanthine oxidase inhibitor compound can induce a positive inotropic effect without increasing energy expenditure, thereby increasing mechanical efficiency. See the examples which follow.
Still further, it has been found that significantly elevated levels of xanthine oxidase activity may exist in subjects suffering from heart failure, relative to control subjects not suffering from heart failure. See, for instance, Example 6 below and FIG. 10 of the drawings, which details a four-fold increase in xanthine oxidase activity in subjects with heart failure, relative to controls. Those results indicate that xanthine oxidase inhibitors can act preferentially in heart failure patients, i.e. that xanthine oxidase inhibitors can boost contractility and efficiency more in failing than normal hearts.
More specifically, methods of the invention include treatment of disorders associated with cardiac contractility, particularly heart failure including congestive heart failure and cardiogenic shock. In one aspect, the treatment methods of the invention in general comprise administration of a therapeutically effective amount of one or more compounds that can increase cardiac contractility to a patient in need of treatment, such as a mammal, particularly a primate such as a human. Preferred compounds for administration include those that inhibit xanthine oxidase (a xanthine oxidase inhibitor).
The invention also includes methods for improving efficiency of cardiac contraction to a patient in need of such treatment. These methods in general comprise administration of an effective amount of a xanthine oxidase inhibitor compound to the patient, particularly an effective amount of allopurinol or oxypurinol. Preferably, a patient will be identified and selected for such treatment, e.g. a patient that is suffering heart failure, including congestive heart failure, where an increase in myocardial contractility with reduced energy requirements is an intended desired therapy.
The methods of the invention include both acute and chronic therapies.
For example, a xanthine oxidase inhibitor can be immediately administered to a patient (e.g. i.p. or i.v.) that has suffered or is suffering from congestive heart failure or cardiogenic shock. Such immediate administration preferably would entail administration of a xanthine oxidase inhibitor within about 1, 2, 4, 8, 12 or 24 hours, or from more than one day to about 2 or three weeks, after a subject has suffered from heart failure such as congestive heart failure or cardiogenic shock.
Relatively long-term administration of a therapeutic agent also will be beneficial after a patient has suffered from chronic heart failure to provide increased exercise tolerance and functional capacity. For example, a xanthine oxidase inhibitor can be administered regularly to a patient for at least 2, 4, 6, 8, 12, 16, 18, 20 or 24 weeks, or longer such 6 months, 1 years, 2 years three years or more, after having suffered heart failure to promote enhanced functional capacity. An oral dosage formulation would be preferred for such long-term administration.
A wide variety of compounds, including xanthine oxidase inhibitors, can be employed in the methods of the invention. For example, suitable xanthine oxidase inhibitor compounds have been previously reported including the compounds disclosed in U.S. Pat. Nos. 5,674,887; 5,272,151; 5,212,201; 4,495,195; 4,346,094; 4,281,005; 4,241,064; 4,179,512; 4,058,614; 4,024,253; 4,021,556; 3,920,652; 3,907,799; 3,892,858; 3,892,738; 3,890,313; 3,624,205; 3,474,098; and 2,868,803.
Specifically preferred therapeutic compounds for use in the methods of the invention include allopurinol (4-hydroxy-pyrazolo[3,4-d]pyrimidine) and oxypurinol (4,6-dihydroxypyrazolo[3,4-d]pyrimidine), and pharmaceutically acceptable salts of those compounds.
Other aspects of the invention are disclosed below.